Use of various nucleoside analogs, and especially acyclic nucleoside analogs in treatment of neoplastic diseases and viral infections has recently gained considerable attention (see e.g., Murono et al. in Cancer Res. 2001 Nov. 1; 61(21):7875-7, or Sekiya et al. in J. Med. Chem. 2002 Jul. 4; 45(14):3138-42). Consequently, synthesis of such nucleoside analogs via hydroxyalkylated heterocyclic bases as key intermediates has become increasingly important, and various methods of preparing hydroxyalkylated heterocyclic bases are known in the art.
For example, Ueda et al. reported the synthesis of 9-hydroxyethyladenine from a reaction in which ethyl carbonate was reacted with adenine using N,N-dimethylformamide (also known as dimethylformamide or DMF) as the solvent (Die Makromolekulare Chemie 1968, 120, 12-20 (Nr.2839)). However, under the conditions employed (i.e., complete removal of the solvent to dryness and recrystallization from ethanol), the total yield of the desired product was only 54%. Moreover, Ueda's conditions led to significant formation of the N7-alkylated byproduct.
In a similar approach, described in U.S. Pat. No. 5,514,798 to Bischofberger et al., which is incorporated herein by reference, 9-hydroxyethyladenine is produced in a reaction between ethyl carbonate and adenine using DMF as a solvent, and the inventors employed a non-polar solvent (toluene) to drive the reaction product from the solvent. While Bischofberger's approach significantly improved the total yield, specificity of the reaction towards the desired N9-hydroxyalkylated product was relatively low and therefore typically required an additional separation step before the reaction product could be employed in further derivatization reactions.
Alternatively, alkylation of a heterocyclic base may be performed following a Mitsunobo reaction as described in U.S. Pat. No. 5,874,577 to Chen et al., wherein linear synthesis starts from 1,3-dioxolane that is subsequently acetylated. Phosphorus is introduced into the so prepared intermediate via reaction with triethoxyphosphine, and the resulting alkylene phosphonate is converted to the corresponding hydroxyalkylene phosphonate, which is then coupled to the heterocyclic base in a Mitsunobu reaction. While Chen's reaction advantageously provides the desired phosphonate nucleoside analog without a hydroxyalkylated intermediate, the total yield was only about 10%, with a selectivity of the Mitsunobu reaction towards the N9-atom of the adenine of only 43%. Similar reaction sequences were reported in Collect. Czech. Chem. Commun. 1989, 54(8), 2190-2210, and in Collect. Czech. Chem. Commun. 1987, 52(11), 2801-2809 with comparable total yields of about 10%, and, depending on the particular conditions, selectivity towards N9-alkylation of the adenine, of between about 11-60%.
Although various methods are known in the art to synthesize various hydroxyalkylated heterocyclic bases, all or almost all of them suffer from one or more disadvantages. Therefore, there is still a need to provide improved synthetic protocols for preparation of hydroxyalkylated heterocyclic bases.